We propose in the Seattle TREC Center to elucidate the pathways linking components of energy balance to the cancer process using several different study designs, with the transdisciplinary contributions of scientists from medicine, cell biology, animal models, epidemiology, nutrition, gastroenterology, molecular biology, obesity, endocrinology, obesity, cardiology, immunology, biostatistics, mathematics, exercise physiology, and behavioral science. The overarching theme of the Seattle TREC Center will be determining the mechanisms by which energy balance modifies and influences the process of carcinogenesis across the lifespan in a broad range of settings including cell culture, animal models, small-scale human experimental studies, and population-level experimental work. In Project 1 we will bring together basic research efforts underway in our laboratories in an innovative approach to analyzing the cellular effects of hyperglycemia, hyperinsulinemia, and inflammation on growth, proliferation and survival pathways relevant to oncogenesis. In Project 2 we will determine, in an animal model, the effects of caloric restriction and exercise, alone and in combination, on the carcinogenic response in the mammary gland and on the mechanisms by which changes in energy balance modulate the development of cancer. In Project 3 we will investigate the metabolic and cancer biomarker response to experimental high and low glycemic load diets in lean and obese teenagers and young adults in a crossover clinical trial design. Within a randomized controlled trial in Project 4, we will investigate the effects of dietary weight loss and exercise, alone and together, on biomarkers of inflammation, and DNA damage and repair, and the influences of genetic polymorphisms on these associations. In Project 5 we will test a worksite obesity prevention intervention in a geographic area with large representation of low income and minority individuals on body mass index and markers of insulin resistance and inflammation. Our novel laboratory work will include testing intervention effects on serum proteomics and, in a developmental project, on metabolomics, in order to identify biological signals of dietary, exercise, and adiposity. Our investigators have a wealth of expertise in the components of the energy balance and cancer equation, and will provide important scientific leadership, training, and contributions to the overall TREC program.